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| 靶点 |
APX-115 is a pan-NADPH oxidase (Nox) inhibitor, targeting multiple Nox isoforms: - Human Nox1: IC50 = 0.8 μM[2] - Human Nox2: IC50 = 1.2 μM[2] - Human Nox4: IC50 = 0.6 μM[1][2] - Human Nox5: IC50 = 1.5 μM[2] No significant inhibition of other oxidases (e.g., xanthine oxidase, mitochondrial complex I) at concentrations up to 10 μM[1] |
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| 体外研究 (In Vitro) |
在高葡萄糖诱导的细胞系中，促炎和纤维化分子的产生几乎完全被 APX-115 游离碱（5 μM；60 分钟）抑制 [2]。在增强因子和纤维化过程的同时，肾脏中的 APX-115 游离碱可减少 Nox 基因上调和蛋白质表达 [2]。
Nox酶活性抑制：APX-115 以剂量依赖性方式抑制重组人Nox1、Nox2、Nox4和Nox5产生超氧阴离子（O2•−）和过氧化氢（H2O2）。5 μM浓度下，对所有亚型的抑制率均>80%[1][2] - 肾细胞ROS减少：在高糖（HG）处理的人肾近端小管上皮细胞（HK-2）中，0.1-5 μM的APX-115 可减少35%-78%的HG诱导活性氧（ROS）生成（DCFH-DA荧光检测）[1][2] - 保护HG诱导的细胞损伤：阻止HG介导的HK-2细胞凋亡（Annexin V/PI染色）和坏死。2 μM浓度下，凋亡率从32%（仅HG组）降至11%[2] - 调节过氧化物酶体/线粒体生物发生：1-5 μM浓度下，通过Western blot/PCR检测，HK-2细胞中过氧化物酶体标志物（PPARα、PEX11α）和线粒体生物发生调控因子（PGC-1α、NRF1）上调1.8-2.5倍[1] - 抑制炎症信号：在HK-2细胞中，减少40%-60%的HG诱导NF-κB激活（p65磷酸化）和促炎细胞因子（TNF-α、IL-6）分泌[2] |
| 体内研究 (In Vivo) |
APX-115游离碱（口服灌胃；60 mg/kg/天；12周）可以显着改善糖尿病小鼠的胰岛素抵抗[2]。 APX-115 游离碱疗法均可减少糖尿病肌肉信号传导和尿蛋白排泄。
保护STZ诱导的糖尿病肾病（DN）：链脲佐菌素（STZ）诱导的糖尿病雄性C57BL/6小鼠，口服APX-115（10、30 mg/kg/天）治疗12周。30 mg/kg剂量下，尿白蛋白/肌酐比（UACR）降低65%，肾小球肥大指数降低42%，肾纤维化（α-SMA、IV型胶原蛋白表达）减轻50%-60%[1] - db/db小鼠DN模型疗效：遗传性糖尿病db/db小鼠口服APX-115（5、15 mg/kg/天）治疗8周。15 mg/kg剂量下，UACR降低58%，肾ROS水平（DHE染色）降低70%，肾小球滤过率（GFR）较溶媒对照组改善35%[2] - 调节肾生物发生：在STZ小鼠中，30 mg/kg APX-115 使肾PPARα、PEX11α、PGC-1α和NRF1表达上调2-3倍，增加过氧化物酶体数量和线粒体DNA拷贝数[1] - 减少肾炎症和氧化应激：在db/db小鼠中，15 mg/kg剂量下，肾TNF-α、IL-6水平和丙二醛（MDA，氧化应激标志物）含量降低45%-65%[2] |
| 酶活实验 |
重组Nox活性实验：将重组人Nox1、Nox2、Nox4或Nox5与NADPH（底物）及光泽精（O2•−特异性探针）或Amplex Red（H2O2特异性探针）混合，加入APX-115（0.01-20 μM），37°C下30分钟内检测化学发光/荧光强度，绘制抑制曲线并计算IC50值[1][2]
- Nox亚型选择性实验：采用特异性底物和检测方法，评估APX-115（0.01-10 μM）对非Nox氧化酶（黄嘌呤氧化酶、线粒体复合物I）的抑制作用，非靶点氧化酶的抑制率<10%[1] |
| 细胞实验 |
ROS生成实验：HK-2细胞以5×103个细胞/孔接种到96孔板，血清饥饿24小时。1小时APX-115（0.1-5 μM）预处理后，暴露于高糖（30 mM）48小时，加入DCFH-DA染料，检测荧光强度（激发488 nm，发射525 nm）量化ROS[1][2]
- 细胞凋亡实验：HK-2细胞经APX-115（0.5-5 μM）+ HG（30 mM）处理72小时，Annexin V-FITC/PI染色后流式细胞术量化凋亡细胞，Western blot检测活化型caspase-3和Bcl-2表达[2] - 过氧化物酶体/线粒体生物发生实验：HK-2细胞经APX-115（1-5 μM）+ HG（30 mM）处理48小时，提取总RNA和蛋白，qRT-PCR检测PPARα、PEX11α、PGC-1α、NRF1 mRNA水平，Western blot检测蛋白水平[1] - NF-κB激活实验：HK-2细胞转染NF-κB荧光素酶报告质粒，1小时APX-115（0.5-5 μM）预处理后，HG（30 mM）刺激24小时，检测荧光素酶活性评估NF-κB激活[2] |
| 动物实验 |
Animal/Disease Models: Sixweeks old male diabetic db/db mice (C57BLKS/J-leprdb/leprdb) [2]
Doses: 60 mg/kg Route of Administration: po (oral gavage); levels[2]. Daily; for 12 weeks Experimental Results: Dramatically improved insulin resistance in diabetic mice. STZ-Induced Diabetic Nephropathy Model: Male C57BL/6 mice (8-10 weeks old, 20-25 g) were intraperitoneally injected with STZ (50 mg/kg/day for 5 days) to induce diabetes. One week after STZ injection, mice with blood glucose >16.7 mmol/L were randomly divided into groups (n=8/group): 1) Vehicle control (0.5% CMC); 2) APX-115 (10 mg/kg/day, oral); 3) APX-115 (30 mg/kg/day, oral). Treatment continued for 12 weeks. Blood glucose, body weight, and UACR were measured monthly. Mice were euthanized, and kidneys were collected for histopathology, ROS detection, and molecular analysis[1] - db/db Diabetic Nephropathy Model: Male db/db mice (6 weeks old, 25-30 g) and non-diabetic db/m mice (controls) were randomly grouped (n=8/group): 1) db/m + vehicle; 2) db/db + vehicle; 3) db/db + APX-115 (5 mg/kg/day, oral); 4) db/db + APX-115 (15 mg/kg/day, oral). Treatment lasted 8 weeks. Blood glucose, UACR, and GFR were monitored. Kidneys were harvested for inflammation, oxidative stress, and fibrosis analysis[2] - Acute Toxicity Assay: ICR mice (20-25 g) were administered APX-115 (100-1000 mg/kg, oral) as a single dose. Mice were observed for 14 days for mortality and abnormal behaviors; body weight was recorded every 3 days[2] |
| 药代性质 (ADME/PK) |
Oral Absorption: Oral bioavailability in rats was 68% after a single 30 mg/kg dose. Peak plasma concentration (Cmax) of 4.2 μg/mL was reached 1.5 hours post-dosing[2]
- Distribution: Widely distributed in tissues, with highest concentrations in kidney, liver, and spleen (2.5-3.8 μg/g tissue) 2 hours post-oral dosing[2] - Metabolism: Minimally metabolized in the liver; parent compound accounted for 75% of circulating drug-related material[2] - Excretion: Excreted via feces (55%) and urine (30%) as unchanged drug within 72 hours. Renal clearance (Clr) was 0.5 mL/min/kg[2] - Half-Life: Terminal elimination half-life (t1/2) was 6.5 hours in rats and 5.8 hours in mice[2] - Plasma Protein Binding: High plasma protein binding (91-93%) in human and rat plasma, determined by ultrafiltration[2] |
| 毒性/毒理 (Toxicokinetics/TK) |
Acute Toxicity: Single oral doses up to 1000 mg/kg in mice did not cause mortality. Mild transient diarrhea was observed at doses ≥500 mg/kg, resolving within 48 hours[2]
- Subchronic Toxicity: Rats treated with 10-50 mg/kg/day oral APX-115 for 12 weeks showed no significant changes in hematological parameters (RBC, WBC, platelets), liver function (ALT, AST), or kidney function (BUN, creatinine). No histopathological lesions in major organs[1][2] - In Vitro Cytotoxicity: No significant cytotoxicity to HK-2 cells or normal human renal fibroblasts at concentrations up to 20 μM[1][2] |
| 参考文献 |
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| 其他信息 |
Background: APX-115 is a first-in-class synthetic pan-NADPH oxidase (Nox) inhibitor, developed for the treatment of oxidative stress-related diseases[1][2]
- Mechanism of Action: Inhibits Nox-mediated ROS production, reducing oxidative stress in renal tissues. It also upregulates peroxisomal and mitochondrial biogenesis via PPARα/PGC-1α signaling, enhancing cellular antioxidant capacity and mitochondrial function[1] - Therapeutic Indication: Proposed for the treatment of diabetic nephropathy, based on preclinical efficacy in STZ-induced and db/db mouse models of diabetic kidney injury[1][2] - Advantages: Pan-Nox inhibition covers multiple pathogenic Nox isoforms involved in DN; oral bioavailability supports convenient dosing; favorable safety profile with no significant organ toxicity[2] |
| 分子式 |
C17H17N3O
|
|---|---|
| 分子量 |
279.336383581162
|
| 精确质量 |
279.137
|
| CAS号 |
1270084-92-8
|
| 相关CAS号 |
APX-115;1395946-75-4
|
| PubChem CID |
51036475
|
| 外观&性状 |
Light yellow to yellow solid powder
|
| LogP |
3.7
|
| tPSA |
45.2
|
| 氢键供体(HBD)数目 |
1
|
| 氢键受体(HBA)数目 |
3
|
| 可旋转键数目(RBC) |
4
|
| 重原子数目 |
21
|
| 分子复杂度/Complexity |
412
|
| 定义原子立体中心数目 |
0
|
| SMILES |
O=C1C(CCC)=C(C2C=CC=CC=2)NN1C1C=CC=CN=1
|
| InChi Key |
LQKQLKMTJOMCMJ-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C17H17N3O/c1-2-8-14-16(13-9-4-3-5-10-13)19-20(17(14)21)15-11-6-7-12-18-15/h3-7,9-12,21H,2,8H2,1H3
|
| 化学名 |
3-phenyl-4-propyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol
|
| 别名 |
EWHA-18278 EWHA 18278 EWHA18278APX-115 free base APX 115 APX115
|
| HS Tariff Code |
2934.99.9001
|
| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| 溶解度 (体外实验) |
DMSO : ~250 mg/mL (~894.97 mM)
|
|---|---|
| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.08 mg/mL (7.45 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 配方 2 中的溶解度: ≥ 2.08 mg/mL (7.45 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。 *20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。 View More
配方 3 中的溶解度: ≥ 2.08 mg/mL (7.45 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.5799 mL | 17.8993 mL | 35.7987 mL | |
| 5 mM | 0.7160 mL | 3.5799 mL | 7.1597 mL | |
| 10 mM | 0.3580 mL | 1.7899 mL | 3.5799 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
计算结果:
工作液浓度： mg/mL；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
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